The present invention relates to a system and a method for imaging and analyzing movements of individual erythrocytes in blood vessels. The system and method according to the present invention are particularly useful in imaging and analyzing the movement of erythrocytes in a retina or the head of the optic nerve, facilitating measurement of blood flow.
Diseases involving the retinal vasculature are one of the leading causes of blindness worldwide. Many of these diseases are both progressive and treatable. Thus, their early detection is highly desirable. Diagnoses are often made on the basis of the many obvious structural changes which may occur in the retina as a consequence of problems with retinal blood flow. These include neovascularization (the growth of new blood vessels in an attempt to compensate for a reduction in flow through pre-existing vessels), cotton-wool patches (regions in which nerve fiber axoplasmic transport has failed), and eventually the degeneration of retinal nerve fibers. Once observed, these and other phenomena may be used to diagnose retinal vascular disease, and treatment may begin to ameliorate further degeneration. However, it is desirable to detect such problems early, if possible, before irreversible damage has occurred.
For the above reason, attention has focused on developing methods of diagnosing retinal vasculature problems by measuring the rate of retinal blood flow, a reduction in which occurs prior to later, more serious, problems. It is desirable for such a method to be rapid, quantitative, and as non-invasive as possible. Film photography fluorescein and indo-cyanine green (ICG) angiography, for example, are commonly used techniques for assessing retinal blood flow. However, fluorescence angiography is a relatively long procedure (e.g., an hour or more), and is not quantitative, which prohibits assembling a database to which the patient""s test results may be readily compared. Fluorescein and ICG angiography require the injection of a large bolus of a fluorescent compound into the bloodstream, a procedure which may have uncomfortable, even dangerous, side effects; and can therefore be administered only when other signs of disease are clearly indicated. Furthermore, only one eye can be carefully followed per injection. Refinement of this technique has improved the quantification of blood flow results, as described in U.S. Pat. Nos. 5,394,199 and 5,437,274, but has retained the disadvantages of invasiveness and, in the case of U.S. Pat. No. 5,394,199, still permits close observation of only one eye.
Another, older, method of measuring retinal blood flow is disclosed in U.S. Pat. No. 4,142,796 and uses the laser Doppler shift effect to detect flow rates at single points. This technique relies on changes in the frequency of light reflected back to a detector from a coherent light source, due to the movement of the target (i.e., blood cells). However, this method does not reveal the overall pattern of blood flow, and so provides only limited information. More recent refinements of this method, disclosed in U.S. Pat. Nos. 5,640,963 and 5,620,000, provide means for moving the laser beam and thus scanning a region of interest, to produce a two-dimensional image. However, use of this technique to date has not found wide acceptance among ophthalmologists, partially because it makes use of an indirect measure of blood flow rates, with uncertain variability in the measurements.
Laser speckle flowgraphy, described in U.S. Pat. Nos. 4,950,070 and 5,090,799, has also been suggested as a means for measuring retinal blood flow. This technique analyzes variations in the reflected light from a laser beam in a small region to determine the rate at which blood is flowing through that region. As for scanning laser Doppler imaging, this technique uses an indirect method to deduce the rate of flow from the signal which is obtained.
Both of the above-described techniques require the use of a laser, a device to scan the laser over the surface of the retina, and a significant number of additional detection optics beyond the basic fundus camera.
Another family of Doppler-effect-based systems is described in U.S. Pat. No. 5,701,898 and relies on shifts in ultrasound frequencies, rather than light frequencies, to determine flow rates. The results, however, are again considered by some ophthalmologists to be difficult to interpret, and do not produce as well-resolved an image as some other techniques.
The common disadvantage of all of the above techniques is that none of them allows the visualization of individual erythrocytes at many sites. Because retinal flow is heterogeneous across different vessels, as well as over a period of time, important diagnostic information may be missed.
The field""s interest in, and the importance of, developing a more direct method of measuring retinal blood flow is further illustrated by a technique published in Investigative Ophthalmology and Visual Science, Vol. 39, pp. 407-415 (February 1988). This technique is a successful means of directly imaging local blood flow and individual erythrocytes; nevertheless, it is highly invasive, requiring surgical incision of the eye and subsequent introduction of an intraocular endoscope. Its eventual clinical utility is therefore extremely restricted.
Thus, there is a need for a diagnostic device which can measure rates of blood flow in a vessel non-invasively, quantitatively and quickly, and which is straightforward enough in interpretation for find general acceptance among medical practitioners for regular use with patients.
It is a broad object of the present invention to provide a system and a method for directly and non-invasively measuring blood flow rates in a vessel.
It is a further object of the invention to provide a method for directly, non-invasively measuring blood flow rates in a vessel by detecting the motion of individual erythrocytes in a bloodstream.
A still further object of the present invention is to provide a method for directly, non-invasively measuring blood flow rates by detecting changes in image reflectance of individual erythrocytes in a bloodstream and determining the rate of flow.
In accordance with the present invention, there is therefore provided a system for directly imaging and analyzing the movement of individual erythrocytes in a blood vessel, comprising imaging means for acquiring, within a predetermined time interval from each other, at least one pair of images of at least one same erythrocyte for producing at least two frames, each image representing an analog or digital image of the location of said erythrocyte in each of said frames at a predetermined time; frame grabbing means for collecting and storing said analog or digital images in machine-readable form, and a computer for controlling the operation of said imaging means and said frame grabbing means, for processing said at least two frames, and for analyzing the movement of said erythrocyte in the blood vessel.
The invention further provides a method for directly imaging and analyzing the movement of individual erythrocytes in blood vessels, said method comprising acquiring, within a predetermined time interval from each other, at least one pair of images of at least one same erythrocyte for producing at least two frames, each image representing an analog or digital image of the location of said erythrocyte in each of said frames at a predetermined time; collecting and storing said analog or digital images in machine-readable form and applying said images to a computer to facilitate processing; performing image-difference analysis on said at least two frames to determine a motion signal resulting from the movement of said erythrocyte, and producing a quantitative measurement of the movement of the erythrocyte in said vessels.
The invention will now be described in connection with certain preferred embodiments with reference to the following illustrative figures so that it may be more fully understood.